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We conducted a phase Ib study to examine the safety of a combination of carbon-ion RT (CIRT) with durvalumab (MEDI4736; AstraZeneca) in patients with locally advanced cervical cancer. This was an open-label, single-arm study with a modified 3 + 3 design. Patients with newly diagnosed histologically proven locally advanced cervical cancer were enrolled. All patients received 74.4 Gy of CIRT in 20 fractions and concurrent weekly cisplatin (chemo-CIRT) at a dose of 40 mg/m2. Durvalumab was administered (1500 mg/body) at weeks two and six. The primary endpoint was the incidence of adverse events (AEs) and serious AEs (SAEs), including dose-limiting toxicity (DLT). All three enrolled patients completed the treatment without interruption. One patient developed hypothyroidism after treatment and was determined to be an SAE. No other SAEs were observed. The patient recovered after levothyroxine sodium hydrate treatment. None of the AEs, including hypothyroidism, were associated with DLT in the present study. All three patients achieved complete responses within the CIRT region concerning treatment efficacy. This phase 1b trial demonstrates the safety of combining chemo-CIRT and durvalumab for locally advanced cervical cancer in the early phase. Further research is required as only three patients were included in this study.

Background and Aims The application of underwater EMR (UEMR) for nonpolypoid superficial nonampullary duodenal epithelial tumors (SNADETs) has not been comprehensively assessed. Therefore, the current study aimed to validate the efficacy of UEMR versus conventional EMR and cap-assisted EMR (EMRC) for SNADETs measuring ≤20 mm. Methods We retrospectively analyzed patients with sporadic nonpolypoid SNADETs measuring ≤20 mm undergoing EMR, EMRC, or UEMR at Chiba University Hospital between May 2004 and October 2020 (EMR, 21 patients and 23 SNADETs; UEMR, 60 patients and 61 SNADETs; EMRC, 45 patients and 48 SNADETs). A weighted logistic regression analysis was performed to analyze outcomes. Univariate and multivariate logistic regression models were used to identify the predictors of RX/1 and piecemeal resection. The recurrence rate of lesions observed ≥12 months after resection was assessed. Results Both UEMR and EMRC had a significantly higher R0 resection rate than EMR. UEMR had significantly lower multiple resection and postbleeding rates than EMR. Only 1 patient (2.1%) who underwent EMRC experienced intraoperative and postoperative perforation. EMR was involved in RX/1 and piecemeal resection. The recurrence rates of EMR, UEMR, and EMRC were 4.3%, 2.0%, and 6.3%, respectively. Conclusions UEMR had significantly higher R0 resection and lower postbleeding rates than EMR. Moreover, it was safer than EMRC and was associated with a lower incidence of recurrences. The significant results of the retrospective analysis suggest a randomized controlled study with adequate numbers needs to be conducted to confirm the superior efficacy of UEMR before it is recommended for primary treatment option for SNADETs measuring ≤20 mm.

Objective To investigate changes in weight following the initiation of antiretroviral therapy in treatment-naive Asian people living with human immunodeficiency virus (PLWH). Methods This retrospective observational study evaluated adult treatment-naive Asian PLWH who started antiretroviral therapy based on an integrase strand transfer inhibitor, a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor at the AIDS Clinical Centre, Tokyo between January 2005 and February 2019. Patients were followed-up until October 2019. Multi-variate linear mixed-effects models were used to generate marginal predictions of weight over time. Predicted weight was reported at 3-month intervals until censoring or for 5 years after treatment initiation. Results Five years after treatment initiation, average weight gain in PLWH who started on dolutegravir-, darunavir- and elvitegravir-based treatment was 5.3 kg, 4.1 kg and 4.6 kg, respectively, while those who started on raltegravir-, lopinavir- and atazanavir-based treatment gained an average of 1.9 kg, 2.1 kg and 2.3 kg, respectively. Average weight gain in PLWH who started treatment with the backbone drugs, tenofovir alafenamide, abacavir and tenofovir disproxil fumarateb was 4.1 kg, 3.0 kg and 3.0 kg, respectively, and those treated with dolutegravir plus tenofovir alafenamide/emtricitabine gained an average of 6.7 kg. Conclusions Antiretroviral-therapy-associated weight gain continued to increase for 5 years following treatment initiation. A combination of dolutegravir and tenofovir alafenamide/emtricitabine was associated with the greatest weight gain.

The mortality of coronavirus disease 2019 (COVID-19) is strongly correlated with pulmonary vascular pathology accompanied by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection–triggered immune dysregulation and aberrant activation of platelets. We combined histological analyses using field emission scanning electron microscopy with energy-dispersive X-ray spectroscopy analyses of the lungs from autopsy samples and single-cell RNA sequencing of peripheral blood mononuclear cells to investigate the pathogenesis of vasculitis and immunothrombosis in COVID-19. We found that SARS-CoV-2 accumulated in the pulmonary vessels, causing exudative vasculitis accompanied by the emergence of thrombospondin-1–expressing noncanonical monocytes and the formation of myosin light chain 9 (Myl9)–containing microthrombi in the lung of COVID-19 patients with fatal disease. The amount of plasma Myl9 in COVID-19 was correlated with the clinical severity, and measuring plasma Myl9 together with other markers allowed us to predict the severity of the disease more accurately. This study provides detailed insight into the pathogenesis of vasculitis and immunothrombosis, which may lead to optimal medical treatment for COVID-19.

Background In double-bundle anterior cruciate ligament reconstruction (ACLR), fixed-loop and adjustable-loop cortical suspensory devices are commonly used to fix the soft graft on the femoral side. However, few studies have compared in vivo elongation of the two devices. The purpose of this study was to determine whether EndoButton CL (EB) and TightRope RT (TR), the suspensory fixation devices used in ACLR, maintained their length in vivo from the time of surgery through the postoperative period in a randomized controlled trial. Methods This study prospectively incorporated 30 patients undergoing initial ACLR at a single center. Participants were divided into two groups using a stratified randomization method with age and sex as assignment adjustment factors. EB or TR was used for fixation of the soft graft on the femoral side. The primary endpoint was to compare the elongation distance of the suspensory device. MRIs were taken within seven days after ACLR and 3,6,12 months postoperatively and measured by a radiologist in a blinded fashion. Secondary endpoints included the side-to-side difference in anterior translation, one leg hop test (HOP index), Lachman test, lateral pivot shift test, and Lysholm score one year postoperatively. Results Twenty-eight patients (EB, n = 13; TR, n = 15) were followed for one year. There was no significant difference between EB and TR groups in elongation from the immediate postoperative period to 3, 6, 12 months after surgery. However, the non-inferiority of TR to EB (non-inferiority margin: 1.5 mm) was not proved by the difference in measured elongation between the two groups (TR – EB, lower 95% CI. AM: 1.80 mm; PL: 1.86 mm) at 6 months. There was no significant difference in anterior translation, HOP index, Lachman test, lateral pivot shift test, or Lysholm score. Conclusion EB and TR had similar graft retaining ability in vivo for 12 months, but the non-inferiority of TR against EB was not verified statistically.

Aims: Diabetic macular edema (DME) leads to impaired vision. The first line of treatment is intravitreal injection of anti-vascular endothelial growth factor (VEGF) agent. However, there are patients who are refractory to this. We reported patients whose DME were refractory to anti-VEGF agents and showed improvement by using sodium glucose cotransporter 2 inhibitors (SGLT2is) . The effectiveness of SGLT2is for DME was assessed using a health insurance claim database. Methods: The JMDC inc. database covering million Japanese patients between 2005-20was used for analysis. Patients with type 2 diabetes (T2D) with DME were included, and those who were undergo dialysis, had other ocular diseases that may be treated by anti-VEGF agents, or were not on treatment with any antidiabetic drug introduced after 2014 were excluded. Propensity score matching was performed between SGLT2i users and non-users. The frequency and the duration of intravitreal injection of anti-VEGF agent after the period from the start of SGLT2is or other antidiabetic drugs were analyzed. Results: In this study, 340 matched patients with T2D were analyzed. Initiation of SGLT2is revealed a decrease in the frequency of anti-VEGF agent injection (2.7 ± 4.1 vs. 3.8 ± 4.6 times, p < 0.001; the Wilcoxon signed rank test, p < 0.001, 95%CI -0.25 to -0.085; the Poisson regression, p < 0.001, HR 0.80, 95% CI 0.73 to 0.87; the recurrent event analysis) and an extension in the duration for the requirement of the first injection of anti-VEGF agent (the number of patients who received no anti-VEGF agents, 96 vs. 32, p < 0.001; the log-rank test) . Conclusion: Using SGLT2is for patients with T2D complicated by DME extended the duration for the requirement of the first anti-VEGF agent injection and decreased the frequency of anti-VEGF agent injection. SGLT2is may be an option for DME treatment. Disclosure R.Ishibashi: Research Support; Astellas Pharma Inc., Boehringer Ingelheim International GmbH, Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Taiho Pharmaceutical Co. Ltd., YL Biologics, ZERIA Pharmaceutical Co.,Ltd. E.Kawakami: None. M.Koshizaka: None. Y.Maezawa: None. K.Yokote: None. Y.Takatsuna: None. T.Tatsumi: None. S.Yamamoto: None. Y.Inaba: None. Y.Shiko: None.

Objective: The purpose of this study was to develop an internet-based Guided Self-Help CBT (iGSH-CBT) for Bulimia Nervosa (BN) / Binge Eating Disorder (BED) for Japanese patients and to test its feasibility with a single-arm study. After baseline assessment, patients underwent a 16-week iGSH-CBT program, our Japanese adaption of the European-based Salut BN program. Evaluations were performed at baseline, after 8 weeks, at the end of the 16-week intervention, and at 2 months after treatment had ended. The primary outcome measure was the change in the weekly frequency of objective binging. Results: Participants were 9 female outpatients with BN (n=5) or BED (n=4), of whom 8 (88.9%) attended the assessment at the end of the 16-week intervention. Percent change of the weekly frequencies of objective binging was -4.40%. Although no significant change was observed in the weekly frequencies of objective bingeing, the abstinence rate from bulimic behaviours of those who completed the assessments was 25.0% at the end of treatment, and the drop-out rate was 11.1%. iGSH-CBT may be an acceptable and possibly even a preferred method of CBT delivery for Japanese patients with BN or BED, and our Japanese adaptation of Salut BN seems feasible.

512 Background: Lenvatinib has been widely used as a leading oral multikinase inhibitor for advanced hepatocellular carcinoma (HCC) patients in real-world practice worldwide. However, in the global phase 3 study comparing the effectiveness of lenvatinib and sorafenib, only a limited population of patients were enrolled, excluding those who had a high-burden intrahepatic lesion or Child-Pugh class (C-P) B, who were likely to receive systemic therapy in the clinical practice. Currently, combination immunotherapy has replaced multikinase inhibitors as the standard first-line treatment. Therefore, this prospective study explored the safety and efficacy of lenvatinib in the patient population, which would be used in real-world practice. Methods: This was an open-label, multicenter, prospective study that enrolled patients who had advanced HCC with C-P A or B, treated with lenvatinib as first-line or second-line after atezolizumab plus bevacizumab (Atz + Bv) at 10 sites in Japan. The study included patients who had high tumor burden, defined as identifying either tumor volume of more than 50% of the liver, portal vein tumor thrombosis reaching the main trunk or the contralateral branch, or bile duct invasion at baseline (jRCTs031190017). Results: Between December 1, 2019, and September 30, 2021, 59 patients were recruited for this study. At the time of enrollment, 47 and 12 patients were classified as C-P A and B, respectively. This study included 11 patients with high tumor burden and 12 treated with second-line after Atz + Bv. All patients with high tumor burden and second-line treatment were classified as C-P A. Median overall survival of C-P A and B patients was 20.3 and 4.2 months, respectively. Similarly, progression-free survival according to modified RECIST (mRECIST) of C-P A and B patients was 4.8 and 2.8 months, respectively. Objective response rate (ORR) according to mRECIST in C-P A patients was 61.9%, whereas in C-P B patients was 25.0%. ORRs of high-burden group and second-line group were 80.0% and 40.0%, respectively. Major severe adverse events (AE) (≥grade 3) in C-P A patients were hypertension (41.3%) and proteinuria (23.9%). In contrast, those in C-P B patients were hyponatremia (41.7%), elevated aspartate aminotransferase (41.7%), hypertension (33.3%), decreased appetite (16.7%), diarrhea (16.7%), and proteinuria (16.7%). Discontinuation rate due to AE of C-P A and B patients was 17.4% and 33.3%, respectively. In high-burden and second-line groups, 10% and 20% discontinued lenvatinib due to AE, respectively. Conclusions: Lenvatinib is expected to be safe and effective in patients with advanced HCC who have a high tumor burden and second-line treatment after Atz + Bv, whereas liver function was maintained with C-P A. However, in C-P B, this study found lower efficacy and higher discontinuation rates due to AE compared with C-P A. Clinical trial information: s031190017 .

Context The syndrome of inappropriate antidiuresis (SIAD) with euvolemic hyponatremia may occur in patients with pulmonary tuberculosis (PTB), but little is known about the clinical characteristics of SIAD-associated hyponatremia in PTB patients. Objective This study aimed to investigate the frequency and risk factors of hyponatremia in PTB patients. Methods In this retrospective chart review, we examined the incidence and severity of hyponatremia in PTB patients. Multivariate analysis was conducted to identify risk factors for hyponatremia in PTB patients. Results Of the 161 patients who were screened, after excluding patients with hyperglycemia and renal failure, we enrolled and analyzed data from 113 participants. Hyponatremia occurred in 40.7% patients ( Conclusions Hyponatremia was less frequently associated with hyperglycemia, heart failure, renal failure, and other diseases that cause euvolemic hyponatremia; thus, PTB patients may have euvolemic hyponatremia due to SIAD. Administration of hypertonic saline or fluid restriction should be considered in PTB patients with hyponatremia.

Purpose Increased use of deep convolutional neural networks (DCNNs) in medical imaging diagnosis requires determinate evaluation of diagnostic performance. We performed the fundamental investigation of diagnostic performance of DCNNs using the detection task of brain metastasis. Methods We retrospectively investigated AlexNet and GoogLeNet using 3117 positive and 37961 negative MRI images with and without metastasis regarding (1) diagnostic biases, (2) the optimal K number of K-fold cross validations (K-CVs), (3) the optimal positive versus negative image ratio, (4) the accuracy improvement curves, (5) the accuracy range prediction by the bootstrap method, and (6) metastatic lesion detection by regions with CNNs (R-CNNs). Results Respectively, AlexNet and GoogLeNet had (1) 50 ± 4.6% and 50 ± 4.9% of the maximal mean ± 95% confidence intervals (95% CIs) measured with equal-sized negative versus negative image datasets and positive versus positive image datasets, (2) no less than 10 and 4 of K number in K-CVs fell within the respective maximum biases of 4.6% or 4.9%, (3) 74% of the highest accuracy with equal positive versus negative image ratio dataset and 91% of that with four times of negative-to-positive image ratio dataset, (4) the accuracy improvement curves increasing from 69% to 74% and 73% to 88% as positive versus negative pairs of the training images increased from 500 to 2495, (5) at least nine and six out of 10-CV result sets essential to predict the accuracy ranges by the bootstrap method, and (6) 50% and 45% of metastatic lesion detection accuracies by R-CNNs. Conclusions Our research presented methodological fundamentals to evaluate diagnostic features in the visual recognition of DCNNs. Our series will help to conduct the accuracy investigation of computer diagnosis in medical imaging.

Background Rocuronium consumption with or without intraoperative objective neuromuscular monitoring in clinical settings of unrestricted use of sugammadex and neuromuscular monitoring has not been reported earlier. The study aimed to investigate the association between the use of intraoperative objective neuromuscular monitoring and rocuronium consumption in patients undergoing laparoscopic abdominal surgery. Methods Data were collected by reviewing electronic medical records of patients who received laparoscopic abdominal surgery under general anesthesia with rocuronium and reversal with sugammadex at a university teaching hospital between May 2017 and April 2018. A multivariate linear regression model was developed to compare the amount of rocuronium consumption (mg) per weight (kg) per hour (mg/kg/h) between the group in which intraoperative objective neuromuscular monitoring was used (NMM+ group) and the group in which intraoperative neuromuscular monitoring was not used (NMM− group). Additionally, we performed an interaction test. Results A total of 429 patients were evaluated, with 371 patients (86%) included in the NMM+ group and 58 patients (14%) in the NMM− group. Log-transformed rocuronium consumption between the NMM+ group and NMM− group was not significantly different (back-transformed β coefficients [95% CI]: 1.080 [0.951-1.226]; P = 0.23). Male sex and body mass index (BMI) were independent factors associated with 15% (0.853 [0.788-0.924]; P < 0.001) and 3% (for every 1 kg/m2 increase in BMI) (0.971 [0.963-0.979]; P < 0.001) decrease in intraoperative rocuronium consumption, respectively. A significant interaction was detected only between the use of neuromuscular monitoring and age ≥65 years (β: 0.803 [0.662-0.974]; P = 0.026). Conclusions Although the use of intraoperative objective neuromuscular monitoring was not an individual factor influencing intraoperative rocuronium consumption, this retrospective study demonstrated that the use of intraoperative neuromuscular monitoring reduced rocuronium consumption for approximately 20% of elderly patients (age ≥65 years) undergoing laparoscopic abdominal surgery.

The appropriate selection of endoscopic resection for relatively small superficial nonampullary duodenal adenomas (SNADAs) considering recurrence is not completely clarified. Therefore, this study investigated endoscopic resection utility (EMR, underwater EMR [UEMR], and cap-assisted EMR [EMRC]) for SNADAs from the viewpoint of recurrence and short-term outcomes.We retrospectively analyzed patients with sporadic SNADAs who underwent EMR, UEMR, and EMRC at Chiba University Hospital between May 2004 and March 2020 and were observed for ≥12 months after endoscopic resection (EMR, 34 patients, 36 lesions; UEMR, 54 patients, 55 lesions; and EMRC, 45 patients, 48 lesions). Outcomes were evaluated using weighted logistic regression analysis. The logistic regression analysis was weighted using propensity scores.EMRC showed significantly higher en-bloc and R0 resection rates than EMR. All techniques were equally safe. Only 1 case each of intraoperative perforation and postoperative perforation (in 2 different patients) occurred, which were associated with EMRC. UEMR resulted in higher R0 resection and lower postbleeding rates than EMR. Moreover, patients who underwent UEMR showed no perforation. Median observation period per lesion after endoscopic resection was 84 months (range, 16-199) for patients who underwent EMR, 25 months (range, 12-60) for patients who underwent UEMR, and 63 months (range, 12-180) for patients who underwent EMRC. No significant difference was observed between EMR versus UEMR and between EMR versus EMRC in terms of recurrence (odds ratio, .20 [95% confidence interval, .01-2.86; P = .24] and .78 [95% confidence interval, .09-6.84; P = .82], respectively).Recurrence risk was not different for EMR, UEMR, and EMRC. Therefore, UEMR, a simple and safe procedure, could be the first choice for relatively small SNADAs. With larger prospective studies, UEMR data may turn out to be more robust, corroborating it as the endoscopic modality of choice for certain SNADAs.

Although primary tumor sidedness (PTS) has a known prognostic role in sporadic colorectal cancer (CRC), its role in Inflammatory Bowel Disease related CRC (IBD-CRC) is largely unknown. Thus, we aimed to evaluate the prognostic role of PTS in patients with IBD-CRC.All eligible patients with surgically treated, non-metastatic IBD-CRC were retrospectively identified from institutional databases at ten European and Asian academic centers. Long term endpoints included recurrence-free (RFS) and overall survival (OS). Multivariable Cox proportional hazard regression as well as propensity score analyses were performed to evaluate whether PTS was significantly associated with RFS and OS.A total of 213 patients were included in the analysis, of which 32.4% had right-sided (RS) tumors and 67.6% had left-sided (LS) tumors. PTS was not associated with OS and RFS even on univariable analysis (5-year OS for RS vs LS tumors was 68.0% vs 77.3%, respectively, p = 0.31; 5-year RFS for RS vs LS tumors was 62.8% vs 65.4%, respectively, p = 0.51). Similarly, PTS was not associated with OS and RFS on propensity score matched analysis (5-year OS for RS vs LS tumors was 82.9% vs 91.3%, p = 0.79; 5-year RFS for RS vs LS tumors was 85.1% vs 81.5%, p = 0.69). These results were maintained when OS and RFS were calculated in patients with RS vs LS tumors after excluding patients with rectal tumors (5-year OS for RS vs LS tumors was 68.0% vs 77.2%, respectively, p = 0.38; 5-year RFS for RS vs LS tumors was 62.8% vs 59.2%, respectively, p = 0.98).In contrast to sporadic CRC, PTS does not appear to have a prognostic role in IBD-CRC.

Background Weight gain after the initiation of antiretroviral therapy (ART) is becoming a major clinical issue in treatment-naïve people living with human immunodeficiency virus (PLWH). However, limited data exist for the Asian populations. We aimed to investigate changes in weight after the initiation of ART therapy in treatment-naïve Asian patients. Methods We evaluated adult, treatment-naïve Asian PLWH who started integrase strand transfer inhibitor (INSTI)-, protease inhibitor (PI)-, or nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART at AIDS Clinical Center, Tokyo, between January 2005 and February 2019. They were followed up until October 2019. Multivariate linear mixed-effects models were used to generate marginal predictions of weight over time. Predicted weight by ART class (INSTI, PI, and NNRTI), each key drug (dolutegravir [DTG], elvitegravir [EVG], raltegravir [RAL], and darunavir [DRV]), and each key drug with or without the use of tenofovir alafenamide (TAF)/emtricitabine (FTC) was reported at 3-month intervals until censoring or 5 years. Results Among the 1,579 study patients, 610 (38.6%), 929 (58.8%), and 40 (2.5%) started INSTI-, PI-, and NNRTI-based ART. After 5 years, PLWH who initiated DTG- (5.3 kg), DRV- (4.0 kg), and EVG-based treatment (4.6 kg) gained more weight than those who initiated RAL-based treatment (1.8 kg). PLWH who initiated DTG plus TAF/FTC (6.7 kg) gained the largest weight. Conclusion In the Asian PLWH population, ART-associated weight gain continues to increase for 5 years after treatment initiation. DTG plus TAF/FTC was associated with the largest weight gain. Disclosures All Authors: No reported disclosures

Supplemental Digital Content is available in the text, This study aimed to identify prognostic factors for severe sepsis-related in-hospital mortality using the structural equation model (SEM) analysis with statistical causality. Sepsis data from the Focused Outcomes Research in Emergency Care in Acute Respiratory Distress Syndrome, Sepsis, and Trauma study (FORECAST), a multicenter cohort study, was used. Forty seven observed variables from the database were used to construct 4 latent variables. SEM analysis was performed on these latent variables to analyze the statistical causality among these data. This study evaluated whether the variables had an effect on in-hospital mortality. Overall, 1148 patients were enrolled. The SEM analysis showed that the 72-hour physical condition was the strongest latent variable affecting mortality, followed by physical condition before treatment. Furthermore, the 72-hour physical condition and the physical condition before treatment strongly influenced the Sequential Organ Failure Assessment (SOFA) score with path coefficients of 0.954 and 0.845, respectively. The SOFA score was the strongest variable that affected mortality after the onset of severe sepsis. The score remains the most robust prognostic factor and can facilitate appropriate policy development on care.

Objectives To determine the mortality and causes of death in people living with HIV (PLHIV) in Japan. Design A prospective cohort study at AIDS Clinical Center, Tokyo, which treats approximately 10% of PLHIV in care in Japan. Methods Either PLHIV who visited our center for the first time between January 2005 and December 2014 or PLHIV who started their regular visit before January 2005 and visited us between January and March 2005 were included and followed by the end of 2016. Causes of death were defined according to the CoDe protocol. Results Two thousand, seven hundred and ninety-seven PLHIV were analysed with total of 18 858 person-years of follow-up, which constitutes 14% of the estimated number of PLHIV in care in Japan. One hundred and sixty-five (5.9%) PLHIV died with all-cause mortality rate of 8.75 per 1000 person-years. All-cause mortality rate for PLHIV in care in Japan was estimated to be 8.75 per 1000 person-years (95% CI 5.53-12.0). Among causes of death, AIDS-defining illnesses accounted for 39% and malignancy contributed to 47%. Standardized mortality ratio (SMR) for all-cause mortality, malignancy-related mortality, and suicide were 5.96 (95% CI 5.05-6.87), 7.76 (95% CI 6.02-9.51), and 3.24 (95% CI 1.54-4.94), respectively. Even among the patients who were diagnosed early or without history of AIDS, SMR was four times higher than the general population. Conclusion Mortality of PLHIV, even among those with early diagnosis, is substantially higher than that of the general population in Japan, highlighting the importance of further efforts towards prevention, early diagnosis and prompt treatment initiation.

Importance The current standard induction therapy for antineutrophil cytoplasm antibody (ANCA)-associated vasculitis is the combination of high-dose glucocorticoids and cyclophosphamide or rituximab. Although these regimens have high remission rates, they are associated with considerable adverse events presumably due to high-dose glucocorticoids. Objective To compare efficacy and adverse events between a reduced-dose glucocorticoid plus rituximab regimen and the standard high-dose glucocorticoid plus rituximab regimen in remission induction of ANCA-associated vasculitis. Design, setting, and participants This was a phase 4, multicenter, open-label, randomized, noninferiority trial. A total of 140 patients with newly diagnosed ANCA-associated vasculitis without severe glomerulonephritis or alveolar hemorrhage were enrolled between November 2014 and June 2019 at 21 hospitals in Japan. Follow-up ended in December 2019. Interventions Patients were randomized to receive reduced-dose prednisolone (0.5 mg/kg/d) plus rituximab (375 mg/m2/wk, 4 doses) (n = 70) or high-dose prednisolone (1 mg/kg/d) plus rituximab (n = 70). Main outcomes and measures The primary end point was the remission rate at 6 months, and the prespecified noninferiority margin was -20 percentage points. There were 8 secondary efficacy outcomes and 6 secondary safety outcomes, including serious adverse events and infections. Results Among 140 patients who were randomized (median age, 73 years; 81 women [57.8%]), 134 (95.7%) completed the trial. At 6 months, 49 of 69 patients (71.0%) in the reduced-dose group and 45 of 65 patients (69.2%) in the high-dose group achieved remission with the protocolized treatments. The treatment difference of 1.8 percentage points (1-sided 97.5% CI, -13.7 to ∞) between the groups met the noninferiority criterion (P = .003 for noninferiority). Twenty-one serious adverse events occurred in 13 patients in the reduced-dose group (18.8%), while 41 occurred in 24 patients in the high-dose group (36.9%) (difference, -18.1% [95% CI, -33.0% to -3.2%]; P = .02). Seven serious infections occurred in 5 patients in the reduced-dose group (7.2%), while 20 occurred in 13 patients in the high-dose group (20.0%) (difference, -12.8% [95% CI, -24.2% to -1.3%]; P = .04). Conclusions and relevance Among patients with newly diagnosed ANCA-associated vasculitis without severe glomerulonephritis or alveolar hemorrhage, a reduced-dose glucocorticoid plus rituximab regimen was noninferior to a high-dose glucocorticoid plus rituximab regimen with regard to induction of disease remission at 6 months. Trial registration ClinicalTrials.gov Identifier: NCT02198248.

The extent and duration of long-term recovery of CD4 count, CD4 percentage (CD4%), and CD4/CD8 ratio after initiation of combination antiretroviral therapy (cART) in patients with a suppressed viral load (VL) are largely unknown.Patients infected with human immunodeficiency virus type 1 who started cART between January 2004 and January 2012 and showed persistent viral suppression (VL,200 copies/mL) for ≥4 years were followed up at the AIDS Clinical Center in Tokyo. Change point analysis was used to determine the time point when CD4 count recovery shows a plateau, and a linear mixed model was applied to estimate the CD4 count at this change point.Data were analyzed from 752 patients (93% male; median age, 38 years; median baseline CD4 cell count, 172/µL [interquartile range CD4%, 13.8%]; CD4/CD8 ratio, 0.23). The median follow-up period was 81.2 months, and 91 patients (12.1%) were followed up for10 years. Change point analysis showed that CD4 count, CD4%, and CD4/CD8 ratio continued to increase until 78.6, 62.2, and 64.3 months, respectively, with adjusted means of 590/µL (95% confidence interval, 29.5%, and 0.89, respectively, at the change point. Although CD4 counts ≥500/μL were achieved in 73.8% of the study patients, they were not achieved in 48.2% of those with a baseline CD4 count100/μL. Neither the CD4% nor the CD4/CD8 ratio were normalized in a majority of patients.The results showed lack of normalization of CD4 count, CD4%, and CD4/CD8 ratio to the levels seen in healthy individuals even after long-term successful cART in patients with a suppressed VL.

Background Although CD4 count is an important marker for prognosis of patients infected with HIV-1, how long and how much CD4 count will increase after initiation of cART are still unknown. Hence, the aim of this study is, using change point analysis, to examine the long-term CD4 count restoration among well-controlled HIV-1 patients. Methods In this single-center cohort study at AIDS Clinical Center, Tokyo, we examined HIV-1 infected patients who initiated cART between January 2004 and January 2012 and achieved HIV viral load of 200 copies/mL, discontinuation of cART for >30 days, lost to follow-up for >1 year, initiating chemotherapy for malignancy, or death), or at end of the observation period (September 30, 2015). Change point analysis was performed to determine the time point where the restoration of CD4 count becomes plateau. Results Of 752 patients, 708 (94.2%) were male and 89.9% was MSM. The median age was 39.3 years [IQR, 32–45] and the median baseline CD4 count and %CD4 were 172 cells/mm3 [IQR, 61–254], and 13.8% [IQR, 7.7–18.5], respectively. The median follow-up period was 87.0 months [IQR, 65.2–109.2] and 134 were followed over ten years. With change point analysis, both longitudinal increase of CD4 count and %CD4 increased linearly until 78.6 and 62.2 months, respectively. Stratified by baseline CD4 count (350 cells/mm3), CD4 count increased linearly until 76.2, 62.4, and 58.6 months, respectively. Moreover, the percentage of patient who achieved 500 cells/mm3 during study period was 63.5%, 87.2%, and 92.0%, respectively. Conclusion With change point analysis, restoration of CD4 count and %CD4 continued increasing linearly until 6.5 and 5 years of cART, respectively. Patients with lower baseline CD4 count showed longer CD4 count recovery than those with higher baseline CD4; however, their CD4 count did not recover as high as those with higher baseline CD4 count. Disclosures All authors: No reported disclosures.

A hidden Markov model (HMM) is a method for analyzing a sequence of transitions for a set of data by considering the outcomes Y to be output from latent state X, which has the Markov property. The HMM has been widely applied, with applications that include speech recognition, genomic analysis, and finance forecasting. The HMM was originally a method for dealing with single-process data. Thus, it is a natural extension to apply it to data with a repeated measure structure by incorporating random effects in it. This is called the mixed hidden Markov model (MHMM). With this extension, the MHMM was recently applied to clinical research data with repeated measurements, e.g. multiple sclerosis, alcohol consumption, and primary biliary cirrhosis. In relation to parameter inference, because regular HMM methods can be used in an MHMM framework, some legacy knowledge is applicable. The likelihood can be obtained by simply adding a random effect parameter to a single process HMM, and the conventional maximum-likelihood method can be used for parameter estimation. On the other hand, much work must still be performed. For instance, the mathematical property of the maximum likelihood estimator has not yet been thoroughly examined. In this study, the asymptotic normality and consistency of the maximum likelihood estimator of the MHMM concerned with time points are examined via simulation, and found that these properties were almost fine. These methods are applied to actual study data, and future perspectives are provided in the conclusion.

2017